While persistent HSV infection has long been recognized as an opportunistic infection in HIV-infected persons, little is known of the natural history of this infection. Serologic evidence of HSV-2 is seen in 40-90% of HIV-1 infected persons and HSV-2 strains that are acyclovir and foscarnet resistant are being reported with increasing frequency. Our preliminary data suggest that HIV-infected persons shed HSV on 10% of all days sampled; a rate 10 times greater than HIV negative persons. 60% of these reactivations are subclinical. HIV-infected pregnant women reactivate HSV at delivery up to 4 times more than HIV-negative women, potentially exposing their infant to the acquisition of neonatal herpes. We have detected HIV-1 in rectal secretions of 22% of subjects with frequent HSV-2 rectal reactivation, suggesting that subclinical HSV shedding may enhance the transmission of HIV. The specific aims of this proposal are to 1) To define the natural history of symptomatic and subclinical reactivation of HSV in HIV-infected persons by defining the anatomic sites, frequency, and duration of symptomatic and subclinical reactivation of HSV among persons co-infected with HSV and HIV. Also, to determine if higher rates of reactivation in HIV seropositive vs HIV seronegative persons are related to differences in viral titer, local host responses, or both. 2) To evaluate the interrelationship between HSV reactivation and HIV replication on mucosal surfaces by determining a) if HSV reactivation increases the frequency and titer of HIV found in rectal secretions and cervical secretions, b) whether genital HSV reactivations at delivery increase the amount of HIV the newborn is exposed to at deliver, and c) if suppression of HSV reactivation will decrease HIV replication on mucosal surfaces. To achieve these objectives, a cohort of HIV-infected men and women will be prospectively followed for evidence of subclinical HSV infection by viral isolation and HSV and HIV DNA and RNA PCR assays. These studies, in concert with those in Projects I, II and IV provide a unique opportunity to study the biology of HSV reactivation and its role as a cofactor in HIV disease.